The present invention relates to a novel process for preparing 6-substituted 5-fluoro-uracil and -cytosine derivatives.
Uracil has been reacted with various compounds to achieve substitution in the 5 position, see "Chlorination of 2,4-Diketotetrahydropyrimidines by Action of Mixture of Superoxol and Hydrochloric Acid", Journal of the American Chemical Society, Vol. 65, part 1, pp. 1218-1219 (1943); "Action of Alkali and Ammonia on 2,4-Dialkoxypyrimidines", Journal of the American Chemical Society, Vol. 56 part 1, pp. 134-139 (1934); "The Reaction of Bromine with Uracils", Journal of Organic Chemistry, Vol. 24, p. 11, Jan. 1959; Wang, "Reaction of Bromine with Uracils", Nature 180, pp. 91-92 (July 13, 1957) and Brown infra.
The reaction of bromine or chlorine with uracil is as follows: ##SPC1##
Numerous references may be cited which demonstrate the extreme reactivity of fluorine in contrast to the other halogens. For example, see M. Hudlicky, "Chemistry of Organic Fluorine Compounds", The MacMillan Co., New York (1962) and J. H. Simons, "Fluorine Chemistry", Vol. 1, Academic Press, Inc., New York, New York (1950). This extreme reactivity and the presumed required intermediacy of a hypohalous acid addition to the double bond would preclude the predictability of the reaction product of the aqueous fluorination of uracil.
The reaction of elemental fluorine with organic compounds has been studied extensively since the discovery of the gas by Henri Moissan in 1886. Moissan found that unlike chlorine, bromine and iodine, the unmoderated reaction of fluorine with organic compounds results in ignition and ultimate decomposition of the organic compound to smaller molecules. This greatly increased reactivity of fluorine compared to the other halogens is readily explained by comparing the heats of reaction of the halogens as in the following reactions. See M. Hudlicky, "Chemistry of Organic Fluorine Compounds", p. 72, The MacMillan Co., New York (1962).
______________________________________ H.degree. (K cal/mole) X = F Cl Br I ______________________________________ C = C + X.sub.2 .fwdarw. CX--CX -107.2 -33.1 -18.8 + 1.2 C -- H + X.sub.2 .fwdarw. C--X+HX -102.5 -22.9 - 6.2 +13.7 ______________________________________
Since the carbon-carbon bond energy is only about 60 K cal/mole, it is quite evident that unless the heat of reaction is removed rapidly the heat evolved in fluorination is more than sufficient to destroy the carbon skelton.
A number of methods have been used in which the heat of reaction is dissipated rapidly enough to give fair yields of fluorinated product. The more common methods are: (1) bubbling a mixture of fluorine and an inert gas through a cold liquid; (2) conducting away the heat of reaction by conducting the reaction in the presence of metal packing; and (3) addition of very large amounts of an inert diluent gas. See M. Stacey, J. C. Tatlow, and A. G. Sharpe, "Advances in Fluorine Chem.", Vol. 2, pp. 196-208, Butterworth, Inc., Washington, D.C. (1961); M. Hudlicky, "Chemistry of Organic Fluorine Compounds", The MacMillan Co., New York (1962); and J. H. Simons, "Fluorine Chemistry", Vol. 1, Academic Press, Inc., New York, N.Y. (1950).
An aqueous medium has seldom been used to assist in fluorination of organic compounds. Reference may be made to the work of Banks, Haszeldine and Lalu, Chem. and Ind. (London), 1803 (1964), CA 62, 428 g. (1965), in which esters of carbamic acid were fluorinated. ##EQU1##
Since uracil exists predominately in the oxo or keto form, see D. J. Brown, "The Pyrimidines", p. 9, Interscience Publishers, Inc., New York (1962), the results of Bank's work would lead one to believe that fluorination of uracil would result in N fluorination rather than C fluorination, i.e., would yield products containing N-F groups. Early work of Heidelberger and Duschinsky reported in U.S. Pat. Nos. 2,802,005 and 3,201,387 indicate that various 6-substituted uracil derivatives are known. Of particular interest is the preparation of 5-fluorocytosine disclosed in the former patent and prepared by refluxing 2-ethylmercapto-4-amino-5-fluoropyrimidine in concentrated aqueous hydrobromic acid. The resulting 5-fluorocytosine and the salts thereof are useful as antimetabolites and to inhibit the growth of various microorganisms. 5-fluorocytosine is a basic compound readily reacting to form addition salts with mineral acids to form pharmaceutically acceptable non-toxic salts. Suitable mineral acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid. Organic acids such as ethanesulfonic acid, toluenesulfonic acid, tartaric acid, citric acid and the like are also used.
It is also known to prepare 5-fluorouracil by reacting uracil mixed with a diluent amount of acetic acid or anhydrous hydrofluoric acid and treating the mixture with fluorine mixed with nitrogen as an inert gas at a temperature of 20.degree. to 25.degree.C; see Belgian Pat. No. 748,468 to Knuniants et al. However, the yield of 5-fluorouracil produced by this process is generally low and the presence of the diluents in the reaction mixture tends to give rise to undesirable secondary reaction products.
As previously stated, the process of the present invention is useful for the preparation of 6-substituted 5-fluoropyrimidine derivatives. The use of 5-fluorouracil in the treatment of cancer, particularly dermatological cancers, is known and well documented. See Heidelberger et al, "Studies on Fluorinated Pyrimidines II -- Effects on Transplanted Tumors", Cancer Research, Vol. 18, p. 305 (1958), and Heidelberger et al, "Fluorinated Pyrimidines, A New Class of Tumor-Inhibitory Compounds", Nature, Vol. 179, p. 663, Mar. 30, 1957. Bardos et al Nature 183, 612 (1959), and Brown, D. J. "The Pyrimidines", p. 175, Interscience, New York (1962). Similarly various cytosine derivatives have been found to be effective antineoplastic and antiviral agents.
The commercially employed method for the synthesis of 5-fluorouracil disclosed in aforesaid U.S. Pat. No. 2,802,005 utilizes extremely toxic monofluoro intermediates. See Stacy et al, "Advances in Fluorine Chemistry", Vol. 2, pp. 196-208, Butterworth, Washington, D.C. (1961). Large scale production has not been undertaken primarily because of the difficulty in handling these intermediates.
It is also known to prepare various uracil derivatives by reacting 5-fluorouracil with chlorine or bromine in the presence of water, as disclosed in Duschinsky et al U.S. Pat. No. 3,277,092. The reaction may be described by the following scheme: ##SPC2##
This procedure requires a separate reduction step to remove the bromine, or chlorine, as the case may be, to produce the uracil derivative, in this case 5-fluoro-6-hydroxy-5,6-dihydrouracil.